title: Aβ monomers transiently sample oligomer and fibril-like configurations: ensemble characterization using a combined MD/NMR approach.
abstract: Amyloid β (Aβ) peptides are a primary component of fibrils and oligomers implicated in the etiology of Alzheimer's disease (AD). However, the intrinsic flexibility of these peptides has frustrated efforts to investigate the secondary and tertiary structure of Aβ monomers, whose conformational landscapes directly contribute to the kinetics and thermodynamics of Aβ aggregation. In this work, de novo replica exchange molecular dynamics (REMD) simulations on the microseconds-per-replica timescale are used to characterize the structural ensembles of Aβ42, Aβ40, and M35-oxidized Aβ42, three physiologically relevant isoforms with substantially different aggregation properties. J-coupling data calculated from the REMD trajectories were compared to corresponding NMR-derived values acquired through two different pulse sequences, revealing that all simulations converge on the order of hundreds of nanoseconds-per-replica toward ensembles that yield good agreement with experiment. Though all three Aβ species adopt highly heterogeneous ensembles, these are considerably more structured compared to simulations on shorter timescales. Prominent in the C-terminus are antiparallel β-hairpins between L17-A21, A30-L36, and V39-I41, similar to oligomer and fibril intrapeptide models that expose these hydrophobic side chains to solvent and may serve as hotspots for self-association. Compared to reduced Aβ42, the absence of a second β-hairpin in Aβ40 and the sampling of alternate β topologies by M35-oxidized Aβ42 may explain the reduced aggregation rates of these forms. A persistent V24-K28 bend motif, observed in all three species, is stabilized by buried backbone to side-chain hydrogen bonds with D23 and a cross-region salt bridge between E22 and K28, highlighting the role of the familial AD-linked E22 and D23 residues in Aβ monomer folding. These characterizations help illustrate the conformational landscapes of Aβ monomers at atomic resolution and provide insight into the early stages of Aβ aggregation pathways.
authors.affiliation: Department of Biology, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY 12180, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Rosenman
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Connors
authors.forename: Wen
authors.initials: W
authors.lastname: Chen
authors.forename: Chunyu
authors.initials: C
authors.lastname: Wang
authors.forename: Angel E
authors.initials: AE
authors.lastname: García
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008954:Models, Biological; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods; D011487:Protein Conformation; D025941:Protein Interaction Mapping / Q000379:methods; D055503:Protein Multimerization; D013816:Thermodynamics
chemical_list: D016229:Amyloid beta-Peptides
keywords: (3)J(HNHA) couplings; AD; Alzheimer's disease; Aβ; CHC; FAD; HSQC; IDP; PCC; PDB; Pearson correlation coefficient; Protein Data Bank; RDC; REMD; amyloid β; central hydrophobic cluster; familial Alzheimer's disease; free-energy landscape; heteronuclear single quantum coherence; iRED; intrinsically disordered protein; isotropic reorientational eigenmode dynamics; molecular dynamics simulations; replica exchange molecular dynamics; residual dipolar coupling; residual dipolar couplings